Parkinson's disease (PD) is a progressive neurodegenerative disease that is typically diagnosed late in its progression. There is a need for biomarkers suitable for monitoring the disease progression at earlier stages to guide the development of novel neuroprotective therapies. One potential biomarker, αsynuclein, has been found in both the familial cases of PD, as well as the sporadic cases and is considered a key feature of PD. α-synuclein is naturally present in the retina, and it has been suggested that early symptoms of the visual system may be used as a biomarker for PD.Here, we use a viral vector to induce a unilateral expression of human wildtype α-synuclein in rats as a mechanistic model of protein aggregation in PD. We employed functional magnetic resonance imaging (fMRI) to investigate whether adeno-associated virus (AAV) mediated expression of human wildtype αsynuclein alter functional activity in the visual system. 16 rats were injected with either AAV-α-synuclein (n=7) or AAV-null (n=9) in the substantia nigra pars compacta of the left hemisphere. The expression of α-synuclein was validated by a motor assay and post-mortem immunohistochemistry. Five months after the introduction of the AAV-vector, fMRI showed robust blood oxygen level dependent (BOLD) responses to light stimulation in the visual systems of both control and AAV-α-synuclein animals.However, our results demonstrate that the expression of AAV-α-synuclein does not affect functional activation of the visual system. This negative finding suggests that fMRI-based read-outs of visual responses may not be a sensitive biomarker for PD. Significance statementWe injected an adeno-associated virus (AAV) vector in rats to induce unilateral expression of human wildtype α-synuclein in the substantia nigra, and in the ipsilateral striatum and superior colliculus (SC). This did not affect functional activation of SC as probed with functional MRI. This negative finding 3 discourages the use of functional brain mapping of visually evoked activity as an indicator of regional expression of human α-synuclein. 55

Biomarkers suitable for early diagnosis and monitoring disease progression are the cornerstone of developing disease-modifying treatments for neurodegenerative diseases such as Parkinson's disease (PD). Besides motor complications, PD is also characterized by deficits in visual processing. Here, we investigate how virally-mediated overexpression of α-synuclein in the substantia nigra pars compacta impacts visual processing in a well-established rodent model of PD. After a unilateral injection of vector, human α-synuclein was detected in the striatum and superior colliculus (SC). In parallel, there was a significant delay in the latency of the transient VEPs from the affected side of the SC in late stages of the disease. Inhibition of leucine-rich repeat kinase using PFE360 failed to rescue the VEP delay and instead increased the latency of the VEP waveform. A support vector machine classifier accurately classified rats according to their `disease state' using frequency-domain data from steadystate visual evoked potentials (SSVEP). Overall, these findings indicate that the latency of the rodent VEP is sensitive to changes mediated by the increased expression of α-synuclein and especially when full overexpression is obtained, whereas the SSVEP facilitated detection of α-synuclein across reflects all stages of PD model progression. Parkinson's disease (PD) is a progressive neurodegenerative disorder affecting ~ 0.2 to 3.0% of the population. It is characterised by the core motor symptoms bradykinesia, resting tremor, rigidity, and postural instability 1,2. PD is also characterized by secondary non-motor symptoms such as hyposmia, constipation, orthostatic hypotension, depression, sleep disorders, decline in cognitive abilities, and deficits in visual processing. Many of these are present already at early stages of PD, whereas classical motor-related symptoms are present in the middle stages 3,4. The pathogenesis of PD develops during prodromal stages of the disease 5. Consequently, there is a high unmet need for validation of new biomarkers that can be used to assess new disease-modifying drug treatments in early or prodromal stages of PD 6. According to the Braak staging hypothesis, PD is a progressive synucleinopathic disorder in which six disease stages are associated with a progressive pathology to neurological structures 7. Pathological hallmarks of PD are the degeneration of dopaminergic neurons in the substantia nigra pars compacta (SNc) 8 and Lewy bodies in addition to 'Lewy neurites': pathological inclusions of aggregated α-synuclein protein in neurons 9,10. Duplications

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The purpose of this study was to pilot an anaesthetic regime with the potential to be used for blood oxygenation level dependent functional magnetic resonance imaging (BOLD fMRI) of the visual system. We used electrophysiology to explore the effect of an anaesthesia regime, combining dexmedetomidine and isoflurane, on the visual system of female Sprague-Dawley rats. This paradigm is hypothesised to affect neural signalling less than other paradigms, and thus may be suitable for studies using BOLD fMRI. Electrodes were implanted bilaterally in the visual cortex (VC) and superior colliculus (SC) of 16 rats. Visual evoked potentials (VEPs) and steady-state VEPs (SSVEPs) were recorded during 1 Hz and 14 Hz light stimulation, respectively. As a control experiment an exploration of the wash-out of isoflurane was performed. The combined anaesthetic regime showed, that the visually evoked responses were almost completely abolished at the initiation of anaesthesia, but gradually recovered to baseline levels over time in the SC. In contrast, the evoked response in the VC only partially recovered, staying significantly below baseline condition. BOLD fMRI results from a previously published study supports this finding.